The present invention relates to a method for using a compound named [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester or a pharmaceutically acceptable salt thereof for the treatment of sebaceous gland disorders. Particularly, methods of treating sebaceous gland disorders are provided, wherein said disorders are selected from seborrhea, acnes, perioral dermatitis, rosacea, and corticosteroid-induced acneiform lesions.
Acne is a group of dermatological disorders which are associated with a variety of etiologies. The group of acnes includes chloroacne, ciliaris, cystic, keratosa, and vulgaris. In its vulgaris form, it occurs primarily in the face and trunk areas, affecting the appearance of the patient. It probably causes more mental pain and anguish to those afflicted than many other diseases which, from a physical standpoint, may be much more severe.
The basic lesion common to the family of diseases referred to as acnes is the comedo or xe2x80x9cblackheadxe2x80x9d of a pilosebaceous follicle. The condition may be mild and transient with only a few blackheads which can readily be ejected by pressure and are of little concern, or may be severe, persistent, and very disfiguring with the more serious cases causing cystic lesions and frequently leaving permanent scarring.
What appears to occur in the development of acnes is an initial filling up of the follicle with a viscous, keratinous material. This impaction of horny material is the whitehead and blackhead. As a result of bacterial growth in these horny impactions, the follicle ruptures initiating the inflammatory phase of the disease which takes the form of pustules, papules, cysts, and nodules. Although many different approaches have been used for the treatment of this affliction, none are universally effective and most possess undesirable side effects.
One of the commonly used methods for acne treatment is the use of xe2x80x9cpeeling,xe2x80x9d i.e., as astringent, agents for mild cases which cause exfoliation with the removal of some of the keratinous plugs. In the more serious cases where pustular or cystic lesions exists, the same are evacuated by incision and the contents expressed. Various other therapies have been employed, such as vaccine therapy, to assist in the control of chronic infection and increase the patient""s resistance to Staphylococci; cortisone-type steroids; hormone therapy, which is applicable only for female patients who may be put on routine contraceptive regimen with estrogens; antibacterial therapy for the treatment of extensive pustular or cystic acne where the patient may be treated with tetracyclines, penicillin, erythromycin, or other of the antibacterial agents, and, in some instances, general surgical skin planing may be used. Systematic administration of hormones and antibacterials has been shown to have some therapeutic merit, but are unacceptable for chronic therapy.
The administration of large oral doses of vitamin A has been suggested as being beneficial in acne (Straumford J. V., xe2x80x9cVitamin A: Its Effects on Acne,xe2x80x9d Northwest Med., August 1943;42:219-225), although other investigators have felt it to be ineffective (Anderson J. A. D. et al., xe2x80x9cVitamin A in Acne Vulgaris,xe2x80x9d Brit. Med J., August 1963;2:294-296; Lynch F. W. et al., xe2x80x9cAcne Vulgaris Treated With Vitamin A,xe2x80x9d Arch Derm., March 1947;55:355, 357; and Mitchell G. H. et al., xe2x80x9cResults of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A,xe2x80x9d Arch. Derm., October 1951;64:428-430).
None of the common topical treatments has been found to be particularly effective. Vitamin A acid has been applied topically (Beer Von P., xe2x80x9cUntersuchungen ber die Wirkung Vitamin A-Saure,xe2x80x9d Dermatologica, March 1962;124:192-195 and Stuttgen G., xe2x80x9cZur Lokalbehandlung von Keratosen mit Vitamin A-Saure,xe2x80x9d Dermatologica, February 1962;124:65-80) achieving good results in those hyperkeratotic disorders which are responsive to high oral doses of vitamin A. Among those treated by Beer and Stuttgen were patients with acne; however, these investigators reported no effective results on this disorder.
The treatment of acnes with isotretinoin and etretinate is described by Goldstein J. A. et al., xe2x80x9cComparative effect of sotretinoin and etretinate on acne and sebaceous gland secretion,xe2x80x9d J. Am Acad Dermatol, 1982;6:760765. Shapiro S. S. et al., discuss treatment of acnes with various potential therapeutic entities in xe2x80x9cEvaluation of Potential Therapeutic Entities for the Treatment of Acnexe2x80x9d Pharmacology of Retinoids in the Skin. Pharmacol. Skin. Reichert and Shroot, eds, Karger, Basel, 1989;3:104-122.
Lambert R. W. and Smith R. E. have discussed the xe2x80x9c[e]ffects of 13-cis-retinoic acid on the hamster Meibomian gland,xe2x80x9d J. Invest Derm, 1989;93(2):321-325 whereas the effects of retinoids on psoriasis is discussed by Lowe N. J. and David M. in xe2x80x9cSystemic Retinoids in Psoriasis: Comparative Efficacy and Toxicity,xe2x80x9d Pharmacology of Retinoids in the Skin. Pharmacol. Skin, Reichert and Shroot eds, Karger, Basel, 1989;3:104-122.
U.S. Pat. No. 3,729,568 refers to the use of vitamin A acid (retinoic acid or tretinoin) in the treatment of acne vulgaris.
International Patent Application PCT/US92/06485 teaches the use of vitamin A acid derivatives in the treatment of skin diseases including acne.
U.S. Pat. No. 4,703,110 describes the use of para substituted benzoic acid derivatives in the treatment of dermatological disorders including cystic acne.
U.S. Pat. No. 4,927,928 teaches the use of benzamido compounds in the treatment of dermatological diseases having an inflammatory and/or immunoallergic component, including acne vulgaris, senile acne, and medicinal or professional acne.
U.S. Pat. No. 4,716,175 granted Dec. 29, 1987, discloses ACAT inhibitors which include the compound named 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)-dodecanamide. The compound has the following structure: 
This patent is hereby incorporated by reference.
European Patent Application Number EP0699439A2 discloses ACAT inhibitors useful for the treatment of sebaceous gland disorders, particularly acne. This application is incorporated herein by reference. The instant compound [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester is not disclosed in EP0699439A2 or in references recited therein.
Compounds that inhibit acyl-coenzyme A: cholesteryl acyltransferase are known as ACAT inhibitors. An ACAT inhibitor, which is [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester and the methods for preparing it, are taught in U.S. Pat. No. 5,491,172 and its divisional 5,633,287, which are hereby incorporated by reference. The compound named [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester is also known by the generic name avasimibe. The use of the compound taught is for treatment of hypercholesterolemia and atherosclerosis.
Methods of using [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester for lowering Lp(a) levels is taught in U.S. Pat. No. 6,117,909.
Methods of using [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester for prevention of plaque rupture is taught in co-pending patent application Ser. No. 60/163,814 filed Nov. 5, 1999.
We have now discovered a surprising and beneficial result. Administration of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester inhibits wax ester synthesis. Thus [2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester has now been discovered to have unexpected benefits useful for the treatment of sebaceous gland disorders, particularly acnes, perioral dermatitis, rosacea, and corticosteroid-induced acneiform lesions. The acne is selected from, for example, chloracne, ciliaris acne, cystic acne, keratosa acne, vulgaris acne, senile acne, and medicinal acne.
The present invention provides a method of treating sebaceous gland disorders comprising administering to a patient in need of said treatment an effective amount of a compound named [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester or a pharmaceutically acceptable salt thereof. It is also understood that the present invention provides a method of treating sebaceous gland disorders in a mammal, especially a human, comprising administering a therapeutically effective amount of a compound named [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-phenyl ester and pharmaceutically acceptable salts thereof.
Particularly, the present invention provides a method of treating sebaceous gland disorders wherein said disorders are selected from acnes, perioral dermatitis, rosacea, and corticosteroid-induced acneiform lesions. The present invention especially provides methods of treating acnes such as, for example, chloracne, ciliaris acne, cystic acne, keratosa acne, vulgaris acne, senile acne, and medicinal acne.